The aims of our proposed research are to determine: 1) the spectrum of cardiorespiratory effects that occur with cocaine administration, 2) the effect of cocaine on cardiovascular changes induced by neurally released and injected catecholamines, 3) whether cocaine augments ventricular irritability and increases susceptibility to sudden death, 4) mechanisms whereby cocaine produces changes in cardiorespiratory function, and 5) the most effective drug(s) for counteracting cocaine-induced cardiorespiratory toxicity. For this purpose cocaine will be administered i.v. to chloralose-anesthetized cats in doses ranging from 0.125 to 8 mg/kg while monitoring arterial pressure, tracheal air flow and tidal volume, heart rate, cardiac rhythm, cardiac output, myocardial contractility, myocardial lactate production, and flows from 3 vascular beds (coronary, renal and mesenteric). Cocaine will also be administered in a cat model of sympathetic mediated coronary constriction and in isolated coronary vessels of pigs. In later studies we will test cocaine in an animal model of coronary spasm. Cocaine will be evaluated on cardiovascular responses elicited by neurally-released and injected catecholamines. The role of presynaptic alpha2- adrenoceptors in modifying all of the above responses produced by cocaine will be examined by repeating experiments in animals pretreated with the alpha 2-adrenoceptor blocker, yohimbine. Cat models of ventricular irritability (coronary occlusion and reperfusion-induced changes in cardiac electrical activity, and imbalanced sympathetic cardiac drive) will be used to evaluate arrhythmogenic properties of cocaine. Mouse models of cardiac sudden death will be employed to determine whether cocaine affects coronary thrombosis. We will use sympathetic nerve recordings, intracerebroventricular injections of cocaine and specific drugs to manipulate the function of brain neurotransmitters for the purpose of elucidating the mechanisms whereby cocaine influences cardiorespiratory function. The information gained will be used as a basis for designing studies to assess which drug(s) is/are best able to counteract cocaine- induced cardiorespiratory toxicity. These studies should: 1) define dose-related cardiorespiratory effects of cocaine, 2) elucidate mechanisms whereby cocaine produces cardiorespiratory effects and 3) provide a foundation for developing drug treatments to both prevent and treat cocaine-induced cardiorespiratory toxicity.